Cell-mediated immunity is critical for host defense against all classes of pathogens and cells that have undergone cancerous transformation. Strategies to vaccinate or potentiate T lymphocyte-mediated cellular immunity have been remarkably ineffective, probably owing to our limited understanding of the mechanisms for establishing and maintaining T cell effector function and memory. This proposal investigates how two T- box family transcription factors contribute to the formation of cellular immunity. Eomesodermin and T-bet redundantly ensure CD8+ T cells become cytotoxic effector cells but they also seem to oppose each other's functions in normal and abnormal CD8+ T cell differentiation. This allows the two transcription factors to form an adjustable balance between the opposing demands of terminal differentiation and self-renewal. The specific aims of this project will address how and when Eomes functions in memory T cell programming. The aims will also resolve whether the predominant actions of Eomes in memory cells are on a unique set of genes or whether Eomes is controlling CD8+ T cell memory through interplay with T-bet at loci they regulate in common. Successful execution of the 3 specific aims of this proposal should provide new insight into the mechanisms of gene induction and cellular differentiation in the immune response. It is also anticipated that these studies will yield new strategies for defending us against a variety of infectious diseases that are the focus of our CD8+ T cell responses. PUBLIC HEALTH RELEVANCE: Specialized white blood cells, called lymphocytes, increase in number to help protect us against infections. This project will provide important information about how these cells are programmed for immediate elimination of infections, how they are trained to provide immunity against re-infection for our entire life, and how they can be re-programmed if they become ineffective.